Abstract
Background: Despite multimodal therapy, Glioblastoma (GBM) chemotherapy with Temozolomide (TMZ) remains inefficient due to chemoresistance. MMP and ADAM metalloproteases (MPs) are increased in GBM and could contribute to chemoresistance and TMZ induced recurrence of glioblastoma. Methods: TMZ sensitivity of GBM cells was assessed with MP inhibitors batimastat (BB-94) and marimastat (BB-2516). Induction of MPs by TMZ was determined by qPCR and activity assays. MP-dependent effects of TMZ on mitochondria and intracellular kinase (Akt/PI3K, ERK1/2) pathway were investigated by FACS, morphological analysis and Western blotting. Invasiveness of TMZ/BB-94 treated GBM cells was determined by Matrigel invasion assays. Potential MP substrates were identified by proteomic analysis and MP expression levels were compared in primary vs. recurrent GBM.
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